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Autonomic pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

Shanbhag, Tara V, MD; Shenoy, Smita, MD;

Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 2, 46-97

Introduction to autonomic nervous system

The nervous system is divided into central nervous system (CNS: brain and spinal cord) and peripheral nervous system (PNS). PNS can be further divided into somatic nervous system and autonomic nervous system (ANS). The differences between these two systems are given in Table 2.1 .

Table 2.1 ■

Differences between ANS and somatic nervous system

Autonomic nervous system	Somatic nervous system
Auto: self; nomos: governing; this system is involuntary and maintains homeostasis	Somatic nervous system is under voluntary control
Each autonomic fibre is made up of two neurons arranged in series	Each somatic fibre is made up of single motor neuron, which connects CNS to skeletal muscles

It innervates the heart, smooth muscles and exocrine glands	It innervates skeletal muscle
It controls visceral functions such as circulation, digestion and excretion	It controls skeletal muscle tone

The ANS has two divisions – sympathetic and parasympathetic. The sympathetic division arises from thoracolumbar region (T ₁ –L ₃ , thoracolumbar outflow) and the parasympathetic division arises from two separate regions in the CNS. The cranial outflow arises from cranial nerves (III, VII, IX and X) and sacral outflow from S ₂ , S ₃ and S ₄ spinal roots.

In sympathetic system, the preganglionic fibres are short and postganglionic fibres are long. On the contrary, the parasympathetic preganglionic fibres are long and postganglionic fibres are short ( Fig. 2.1 ). Most of the visceral organs have dual nerve supply, i.e. they are supplied by both divisions of the ANS, but effects of one system predominate. The ciliary muscle, pancreatic and gastric glands receive only parasympathetic supply; sweat glands, hair follicles, spleen and most of the blood vessels have only sympathetic supply. Their stimulation usually produces opposite effect on the innervating organ ( Fig. 2.2 ).

Cholinergic system PH1.14

Cholinergic transmission

Acetylcholine (ACh) is the neurotransmitter in the cholinergic system. The sites of cholinergic transmission are shown in Fig. 2.1 . The neurons that synthesize, store and release ACh are called cholinergic neurons.

Synthesis of acetylcholine ( fig. 2.3 )

Choline enters the cholinergic neuron by carrier-mediated transport, where it reacts with acetyl-CoA with the help of choline acetyltransferase (ChAT) to form ACh. The ACh is then stored in storage vesicles. It is released into synaptic cleft when an action potential reaches the nerve terminals. The released ACh interacts with cholinergic receptors on effector cell and activates them. In the synaptic cleft, ACh is rapidly hydrolysed by acetylcholinesterase (AChE) enzyme.

Cholinesterases

ACh is rapidly hydrolysed to choline and acetic acid by enzyme cholinesterases. There are two types of cholinesterase:

1.
True cholinesterase or AChE: It is found in cholinergic neurons, ganglia, RBCs and neuromuscular junction (NMJ). It rapidly hydrolyses ACh and methacholine.
2.
Pseudocholinesterase or butyrylcholinesterase: It is found in plasma, liver and glial cells. Pseudocholinesterase can act on a wide variety of esters including ACh (hydrolysis is slow) but does not hydrolyse methacholine.

Cholinergic receptors

They are divided broadly into two types – muscarinic and nicotinic. Muscarinic receptors are further divided into five different subtypes: M ₁ –M ₅ . Only M ₁ , M ₂ and M ₃ are functionally recognized. M ₄ and M ₅ subtypes are found in CNS. All muscarinic receptors are G-protein–coupled receptors and regulate the production of intracellular second messengers.

Nicotinic receptors are divided into two subtypes – N _N and N _M . Activation of these receptors directly opens ion channels and causes depolarization of the membrane. The characteristics of muscarinic and nicotinic receptors are shown in Table 2.2 .

Table 2.2 ■

Characteristics of muscarinic and nicotinic receptor subtypes

Receptor type(s)	Intracellular effects	Response
M ₁ and M ₃	↑ Inositol triphosphate (IP ₃ ) and ↑ diacylglycerol (DAG)	• Increases learning and memory • Promotes glandular secretion and smooth muscle contraction
M ₂	↓ Cyclic adenosine monophosphate (cAMP), opening of K ⁺ channels	Hyperpolarization • Depresses SA node • Depresses AV node • Decreases atrial and ventricular contraction
N _N	Opening of ion channels (Na ⁺ , K ⁺ )	Depolarization • Release of adrenaline and noradrenaline from adrenal medulla
N _M	Opening of ion channels (Na ⁺ , K ⁺ )	• Depolarization • Skeletal muscle contraction

Cholinergic agents (cholinomimetics, parasympathomimetics) PH1.14

ACh is a quaternary ammonium compound and is rapidly hydrolysed by cholinesterases. Hence, it has no therapeutic application. It has to be given intravenously to study its pharmacological actions. Even when given intravenously, a large amount of the drug is destroyed by pseudocholinesterase in blood.

Classification

Choline esters

Choline esters include ACh, carbachol and bethanechol.

Acetylcholine.

ACh produces muscarinic and nicotinic effects by interacting with respective receptors on the effector cells ( Table 2.3 ).

Table 2.3 ■

Pharmacological properties and uses of choline esters

	Acetylcholine	Carbachol	Bethanechol
Metabolized by	True and pseudocholinesterase enzymes	Resistant to both enzymes	Resistant to both enzymes
Muscarinic actions	+	+	+
Nicotinic actions	+	+	−
Effect of atropine	Muscarinic actions are completely blocked by atropine	Muscarinic actions are not completely blocked by atropine	Muscarinic actions are completely blocked by atropine
Uses	Not useful in therapy because of very short duration of action	Glaucoma	More selective for bladder and GIT – useful in postoperative urinary retention and paralytic ileus

+, present; –, absent.

Muscarinic actions

1.
Cardiovascular system
- (a)
  Heart: The effects of ACh are similar to those following vagal stimulation. ACh, by stimulating M ₂ receptors of the heart, opens K ⁺ channels resulting in hyperpolarization. Therefore, SA and AV nodal activity is reduced ( Fig. 2.4 ).
  Fig. 2.4
  Effects of acetylcholine (ACh) on heart. HR, heart rate; FOC, force of contraction.
- (b)
  Blood vessels: ACh stimulates M ₃ receptors of vascular endothelial cells, which release endothelium-dependent relaxing factor (EDRF; NO) leading to vasodilatation and a fall in blood pressure (BP) ( Fig. 2.5 ).
  Fig. 2.5
  The effect of acetylcholine (ACh) on blood vessels.
2.
Smooth muscles
- (a)
  Gastrointestinal tract ( Fig. 2.6 )
  Fig. 2.6
  Effects of acetylcholine (ACh) on gastrointestinal (GI) tract.
- (b)
  Urinary bladder ( Fig. 2.7 )
  Fig. 2.7
  Effects of acetylcholine (ACh) on urinary bladder.
- (c)
  Bronchi ( Fig. 2.8 )
  Fig. 2.8
  The effect of acetylcholine (ACh) on bronchi.
3.
Exocrine glands: Increase in salivary, lacrimal, sweat, bronchial, gastric and other gastrointestinal (GI) secretions.
4.
Eye ( Fig. 2.9 ): ACh does not produce any effect on topical administration because of its poor penetration through tissues.
Fig. 2.9
Autonomic innervation of the eye.

Action of muscarinic agonists on eye can be depicted as follows:

Nicotinic actions.

To elicit nicotinic actions, larger doses of ACh are required.

1.
Autonomic ganglia: Higher doses of ACh produce dangerous muscarinic effects especially on the heart. Hence, prior administration of atropine is necessary to elicit nicotinic actions.
- Higher doses of ACh stimulate both sympathetic and parasympathetic ganglia ( Fig. 2.10 ) causing tachycardia and rise in BP.
  Fig. 2.10
  Stimulation of parasympathetic and sympathetic ganglia.
2.
Skeletal muscles: At high concentration, ACh initially produces twitching, fasciculations followed by prolonged depolarization of NMJ and paralysis.
3.
Actions on CNS: Intravenously administered ACh does not cause any central effects because of its poor penetration through the blood–brain barrier (BBB).

Bethanechol (table 2.3).

It has selective muscarinic actions on GIT and urinary bladder. It is preferred in postoperative urinary retention and paralytic ileus.

Cholinomimetic alkaloids

They mimic the actions of ACh; examples are pilocarpine, muscarine and arecoline.

Pilocarpine.

Pilocarpine is a cholinomimetic alkaloid obtained from Pilocarpus plant. It is a tertiary amine. It produces muscarinic and nicotinic effects by directly interacting with the receptors. It has predominant muscarinic actions especially on secretory activity.

Uses

1.
Pilocarpine 0.5%–4% solution is used topically in the treatment of open-angle glaucoma and acute congestive glaucoma . It increases the tone of the ciliary muscle and causes miosis by contracting sphincter pupillae, opens the trabecular meshwork around the canal of Schlemm, facilitates drainage of aqueous humour and reduces intraocular pressure (IOP). It acts rapidly but has short duration of action. Pilocarpine ocusert that releases the drug slowly over 7 days is available (see p. 8).
2.
It is used alternatively with mydriatics to break adhesions between the iris and lens .
3.
It is used to reverse the pupillary dilatation after refraction testing.
4.
Pilocarpine is used as a sialagogue (drug used to augment salivary secretion).

Adverse effects.

They are salivation, sweating, bradycardia, diarrhoea and bronchospasm; pulmonary oedema can occur following systemic therapy.

Muscarine.

It is an active ingredient of poisonous mushroom, Amanita muscaria and Inocybe species. Some types of mushroom poisoning are explained as follows:

Treatment of mushroom poisoning is mainly supportive.

Arecoline.

It is an alkaloid obtained from areca nut. It has muscarinic and nicotinic actions similar to choline esters.

Anticholinesterases ( fig. 2.11 )

They inhibit the enzyme cholinesterase that is responsible for hydrolysis of ACh. Thus, ACh is not metabolized, gets accumulated at muscarinic and nicotinic sites and produces cholinergic effects. Hence, anticholinesterases are called indirectly acting cholinergic drugs.

Mechanism of action: ACh is rapidly hydrolysed by both true and pseudocholinesterases. ACh binds to anionic and esteratic sites of cholinesterase → acetylated enzyme → undergoes rapid hydrolysis → acetate and free enzyme.

■
Carbamates bind to both the sites (i.e. anionic and esteratic) of cholinesterase (so ACh cannot bind the enzyme) → carbamoylated enzyme → undergoes slow hydrolysis to release the enzyme.
■
Edrophonium binds only to anionic site of ChE. It forms weak hydrogen bond with the enzyme. It diffuses away from the enzyme. Duration of action is 8–10 minutes.
■
Organophosphates bind covalently to esteratic site of cholinesterases and inhibit them irreversibly as hydrolysis of phosphorylated enzyme is extremely slow. Echothiophate binds to both anionic and esteratic sites of the enzyme.

Reversible anticholinesterases

■
Physostigmine
■
Neostigmine
■
Pyridostigmine
■
Edrophonium
■
Galantamine
■
Rivastigmine
■
Donepezil
Reversible anticholinesterases inhibit both true and pseudocholinesterases reversibly.

Physostigmine (eserine).

It is an alkaloid obtained from Physostigma venenosum . It is a tertiary amine and has good penetration through tissues. Its actions are similar to those of other cholinergic agents.

Uses

1.
Glaucoma: Physostigmine reduces IOP by producing miosis, thus facilitates the drainage of aqueous humour. On chronic use, it accelerates cataract formation; hence, it is rarely used in glaucoma.
2.
Atropine poisoning: Intravenous physostigmine is used for severe atropine and other antimuscarinic drug poisoning because it has both central and peripheral actions. It competitively reverses the effects of atropine poisoning, but it should be used cautiously by slow i.v. injection as it may cause bradycardia.

Neostigmine ( table 2.4 ; see fig. 2.13 ).

Neostigmine is a synthetic anticholinesterase agent. Its actions are pronounced on NMJ, gastrointestinal tract (GIT) and urinary bladder than on cardiovascular system (CVS) or eye. On skeletal muscle, it has both direct and indirect actions.

Table 2.4 ■

Comparative features of physostigmine and neostigmine

Physostigmine	Neostigmine
Natural alkaloid obtained from Physostigma venenosum	Synthetic agent
Tertiary amine, has good penetration through tissues, hence topically effective	Quaternary ammonium compound, has poor penetration, hence topically not effective
Crosses BBB – produces both central and peripheral effects	Does not cross BBB, hence no central effects
Uses • Atropine poisoning • Glaucoma	Uses • Postoperative urinary retention and paralytic ileus • Myasthenia gravis • Curare poisoning

Indirect actions.

By inhibiting cholinesterases, neostigmine increases ACh concentration at NMJ.

Direct actions.

Because of structural similarity with ACh (i.e. quaternary ammonium compound), neostigmine also directly stimulates N _M receptors at NMJ. Thus, it improves muscle power in patients with myasthenia gravis.

Neostigmine does not cross BBB and has no central side effects. Therefore, neostigmine is preferred to physostigmine in myasthenia gravis. It is available for oral, s.c., i.v. and i.m. administration.

Pyridostigmine.

All features are same as neostigmine. Pyridostigmine has a longer duration of action and can be given twice daily in sustained release form; hence, it is preferred to neostigmine in myasthenia gravis. Even though pyridostigmine is less potent than neostigmine, it is better tolerated by myasthenic patients.

Edrophonium.

It is a quaternary ammonium compound. On i.v. administration, it has a rapid onset but short duration of action (8–10 minutes).

Uses

1.
Edrophonium is used in the diagnosis of myasthenia gravis.
2.
It is used to differentiate myasthenic crisis from cholinergic crisis.
3.
In curare poisoning, edrophonium is preferred because of its rapid onset of action.

Adverse effects of anticholinesterases.

They are due to overstimulation of both muscarinic and nicotinic receptors – increased sweating, salivation, nausea, vomiting, abdominal cramps, bradycardia, diarrhoea, tremors and hypotension.

Therapeutic uses of reversible anticholinesterases

1.
Eye
- (a)
  Glaucoma
- (b)
  To reverse pupillary dilatation after refraction testing
- (c)
  Miotics are used alternatively with mydriatics to break adhesions between iris and lens
2.
Myasthenia gravis
3.
Postoperative urinary retention and paralytic ileus
4.
Curare poisoning and reversal of nondepolarizing neuromuscular blockade
5.
Belladonna poisoning
6.
Alzheimer’s disease

1. Glaucoma.

The aqueous humour formed by ciliary process is drained mainly through trabecular meshwork ( Fig. 2.12 ).

Glaucoma is optic nerve damage with loss of visual function that is frequently associated with raised IOP. Normal IOP varies between 10 and 20 mm Hg. Management of this disorder is almost always directed at lowering the existing IOP either by improving drainage or decreasing the formation of aqueous humour ( Fig. 2.12 ).

Acute congestive glaucoma: It is usually precipitated by mydriatics in people with narrow iridocorneal angle and shallow anterior chamber. Acute congestive glaucoma is a medical emergency. Once the attack is controlled, treatment is surgical or laser iridotomy.

Chronic simple glaucoma: It is a genetically predisposed condition affecting the patency of trabecular meshwork. The IOP rises gradually. Pharmacotherapy is the definitive treatment in a majority of cases.

Drugs for glaucoma ( Table 2.5 )

1.
Osmotic agents: Mannitol (20%) i.v. infusion (1.5 g/kg body weight) and 50% glycerol oral (1.5 g/kg) are used. They draw fluid from the eye into the circulation by osmotic effect and reduce IOP in acute congestive glaucoma.
2.
Carbonic anhydrase inhibitors: Acetazolamide (oral, i.v.), dorzolamide (topical) and brinzolamide (topical) are carbonic anhydrase inhibitors. They inhibit carbonic anhydrase enzyme, decrease bicarbonate formation in ciliary epithelium and decrease the formation of aqueous humour. Topical carbonic anhydrase inhibitors, which have a much lower risk of systemic side effects, are preferred to systemic carbonic anhydrase inhibitors in chronic simple glaucoma. In acute congestive glaucoma, acetazolamide is administered intravenously and orally.
3.
β -Adrenergic blockers: Topical nonselective β-blockers are timolol, betaxolol, levobunolol and carteolol. They decrease aqueous humour formation by blocking β ₂ -receptors on ciliary epithelium. β-Blockers also decrease ocular blood flow. Timolol is widely used in glaucoma because (i) it lacks local anaesthetic or partial agonistic properties; (ii) it does not affect pupil size or accommodation; (iii) it has longer duration of action; (iv) it is well tolerated; (v) it is less expensive. Topical timolol is safer and highly effective. Betaxolol is a selective β ₁ -blocker used in glaucoma, but it is less effective than nonselective agents. Betaxolol is protective to retinal neurons. Levobunolol is long acting. β-Blockers should be cautiously used in patients with bronchial asthma and heart failure.
4.
Prostaglandins (PGs): They reduce IOP probably by facilitating uveoscleral outflow. Topical PGs such as latanoprost, travoprost and bimatoprost (PGF ₂ α-analogues) are the drug of choice in open-angle glaucoma because of their longer duration of action (once a day dosing), high efficacy and low incidence of systemic toxicity. They are also useful in acute congestive glaucoma. Latanoprost is also available in combination with timolol. They usually do not cause systemic side effects but may cause ocular irritation and iris pigmentation.
5.
Miotics: Pilocarpine is a tertiary amine and is well absorbed through cornea. It is used topically in the treatment of open-angle and acute congestive glaucoma. It facilitates drainage of aqueous humour and reduces IOP.
6.
α-Adrenergic agonists
- (a)
  Apraclonidine is used topically as an adjunct in glaucoma. It does not cross the BBB, hence has no hypotensive effect like clonidine. They act on α ₂ -receptors on ciliary epithelium.
- (b)
  Dipivefrin is a prodrug of adrenaline. It penetrates the cornea and with the help of esterases, gets converted into adrenaline.

Table 2.5 ■

Drugs used for treating glaucoma

Acute congestive (narrow-angle) glaucoma	Chronic simple (wide-angle) glaucoma
Osmotic agents • Mannitol (20%) i.v. • Glycerol (50%) oral	β-Blockers * (topical) • Timolol (0.25%) • Betaxolol (0.25%) • Carteolol (1%)
Carbonic anhydrase inhibitor • Acetazolamide, i.v., oral	Prostaglandins • Latanoprost (0.005%), topical
β-Blockers • Timolol (0.5%), topical	Carbonic anhydrase inhibitors • Dorzolamide (2%), topical • Brinzolamide, topical • Acetazolamide, oral
Miotics • Pilocarpine (2%), topical	α-Adrenergic agonists • Dipivefrin (0.1%), topical • Apraclonidine (1%), topical
Prostaglandins • Latanoprost (0.005%), topical	Miotics • Pilocarpine (0.5%), topical

* Propranolol is not used in glaucoma as it anesthetizes cornea due to its membrane stabilizing effect

2. Myasthenia gravis.

Myasthenia gravis is an autoimmune disorder where antibodies are produced against N _M receptors of NMJ resulting in a decrease in the number of N _M receptors. There is an increased incidence of myasthenia gravis in patients with thymoma. Thymectomy can induce remission in most of the cases. In myasthenia, there is marked muscular weakness varying in degree at different times. Myasthenia gravis is diagnosed by:

1.
Typical signs and symptoms – weakness and easy fatigability.
2.
Edrophonium test – edrophonium (2–10 mg) given slow intravenously shows dramatic improvement of symptoms in patients with myasthenia gravis but not in other muscular dystrophies; it is also useful to differentiate myasthenic crisis from cholinergic crisis.
3.
Demonstration of circulating antibodies to N _M receptors.

Treatment.

Anticholinesterases (neostigmine, pyridostigmine and ambenonium) are effective in providing symptomatic relief. They inhibit metabolism of ACh, thus prolonging its action at the receptors. Neostigmine also directly activates the N _M receptors. Pyridostigmine is commonly used.

Long-term use or overdose of anticholinesterases leads to cholinergic crisis (severe muscular weakness and neuromuscular paralysis due to prolonged depolarization). This may be differentiated from myasthenic crisis (severe weakness due to exacerbation of myasthenia) by injecting a small dose of edrophonium (2 mg, i.v.). If the patient shows improvement in muscle power → myasthenic crisis. If the muscular weakness deteriorates → cholinergic crisis. Ventilator should be kept ready before injecting edrophonium as it may aggravate cholinergic crisis, which is dangerous.

Corticosteroids and other immunosuppressants like azathioprine or cyclophosphamide are useful in the induction and maintenance of remission. Plasmapheresis and immune therapy may be useful in resistant cases.

Note: Drugs that aggravate myasthenia (drugs that are contraindicated in myasthenia) are aminoglycoside antibiotics, d-tubocurarine (d-TC) and other neuromuscular blockers, β-blockers, ether, phenytoin, etc.

3. Postoperative urinary retention and paralytic ileus ( fig. 2.13 ).

Neostigmine is used because it increases the tone of the smooth muscle and relaxes the sphincters.

4. Curare poisoning and reversal of nondepolarizing neuromuscular blockade (see p. 74).

Edrophonium or neostigmine is used. They antagonize neuromuscular blockade by increasing the concentration of ACh at the NMJ. Prior administration of atropine is a must to block the muscarinic side effects.

5. Belladonna poisoning (see p. 67).

Physostigmine is preferred because it reverses both central and peripheral effects of atropine poisoning.

6. Alzheimer’s disease.

It is a degenerative disease of the cerebral cortex. Donepezil, galantamine and rivastigmine are cerebroselective anticholinesterases. They increase cerebral levels of ACh and have shown to produce some benefit in these patients.

Irreversible anticholinesterases PH1.51, PH1.52

Organophosphorus insecticides.

All organophosphorus (OP) compounds except echothiophate have no therapeutic applications. Echothiophate is rarely used in resistant cases of glaucoma. OP compounds have only toxicological importance.

OP poisoning is one of the most common poisoning all over the world. Common OP compounds are parathion, malathion, dyflos, etc. They irreversibly inhibit cholinesterases and cause accumulation of ACh at muscarinic and nicotinic sites.

Signs and symptoms

1.
Muscarinic effects: Profuse sweating, salivation, lacrimation, increased tracheobronchial secretions, bronchospasm, vomiting, abdominal cramps, miosis, bradycardia, hypotension, involuntary urination and defecation.
2.
Nicotinic effects: Twitchings, fasciculations, muscle weakness and paralysis are due to prolonged depolarization.
3.
Central effects: Headache, restlessness, confusion, convulsions, coma and death are usually due to respiratory failure.

Diagnosis.

OP poisoning can be diagnosed by:

■
History of exposure
■
Characteristic signs and symptoms
■
Estimating the cholinesterase activity in blood, which is decreased

Treatment.

General measures

1.
Remove the contaminated clothes; wash skin with soap and water.
2.
Gastric lavage should be continued till the returning fluid is clear.
3.
Airway should be maintained.
4.
Artificial respiration is given, if necessary.
5.
Diazepam should be used cautiously by slow i.v. injection to control convulsions.

Specific measures

1.
Atropine: Atropine is the first drug to be given in OP poisoning. Inject atropine 2 mg i.v. stat and it should be repeated every 5–10 minutes doubling the dose, if required, till the patient is fully atropinized (fully dilated, nonreactive pupils, tachycardia, etc.). Atropine should be continued for 7–10 days.
- Atropine competitively blocks the muscarinic effects of OP compounds (competitive antagonism).
2.
Oximes: Atropine is not effective for reversal of neuromuscular paralysis. Neuromuscular transmission can be improved by giving cholinesterase reactivators such as pralidoxime and obidoxime. Pralidoxime is administered intravenously slowly in a dose of 1–2 g.

As shown above, OP compounds inactivate cholinesterases by phosphorylating esteratic site of the enzyme. Oximes bind with high affinity to anionic site, react with phosphorus atom of the OP compound, dephosphorylate the enzyme, and reactivate it. Early administration of oximes is necessary before the phosphorylated enzyme undergoes ‘aging’ (loses alkyl groups) and becomes resistant to reactivation.

Oximes are not effective in carbamate poisoning; they also have mild anti-ChE activity

Delayed toxicity of organophosphates: Prolonged exposure to OP compounds can cause neurotoxicity.

Anticholinergic agents PH1.14

Various anticholinergic agents are shown as follows:

Generally, anticholinergics refer to antimuscarinic drugs.

Antimuscarinic agents (muscarinic receptor antagonists) PH1.14

These drugs block muscarinic receptor mediated actions of ACh on heart, CNS, smooth muscles and exocrine glands. Atropine and scopolamine are belladonna alkaloids. Atropine is obtained from Atropa belladonna and scopolamine from Hyoscyamus niger .

Mechanism of action.

Both natural and synthetic drugs competitively block the muscarinic effects of ACh (competitive antagonism).

Classification of antimuscarinic agents

1.
Natural alkaloids ( Belladonna alkaloids ): Atropine, scopolamine (hyoscine).
2.
Semisynthetic derivatives:
- Hyoscine butyl bromide
- Homatropine (mydriatic)
- Ipratropium bromide, tiotropium bromide (bronchial asthma)
3.
Synthetic antimuscarinic agents:
- (a)
  Used as mydriatic – cyclopentolate, tropicamide
- (b)
  Used in peptic ulcer – pirenzepine, telenzepine, clidinium, propantheline
- (c)
  Used as antispasmodic – dicyclomine, valethamate, flavoxate, oxybutynin, tolterodine, darifenacin
- (d)
  Used as preanaesthetic agent – glycopyrrolate
- (e)
  Used in parkinsonism – benzhexol (trihexyphenidyl), benztropine, biperiden, procyclidine

Atropine.

Atropine is the prototype drug and the chief alkaloid of belladonna. It is a tertiary amine. It blocks actions of ACh on all the muscarinic receptors. Atropine is administered by topical (eye), oral and parenteral routes.

Pharmacological actions of atropine ( fig. 2.14 )

1.
CNS: In therapeutic doses, atropine has mild CNS stimulant effect. It produces antiparkinsonian effect by reducing cholinergic overactivity in basal ganglia. It suppresses vestibular disturbances and produces antimotion sickness effect. Large doses can produce excitement, restlessness, agitation, hallucinations, medullary paralysis, coma and death.
2.
CVS: At low doses, atropine causes initial bradycardia due to blockade of presynaptic muscarinic autoreceptors (M ₁ ) on vagal nerve endings. In therapeutic doses, tachycardia is seen due to blockade of M ₂ receptors of the heart; it also improves A–V conduction. In high doses, flushing of the face and hypotension may occur due to cutaneous vasodilatation.
3.
Glands: All secretions under cholinergic influence are reduced due to blockade of M ₃ receptors, i.e. sweat, salivary, nasal, throat, bronchial, gastric, lacrimal, etc. Milk and bile secretions are not affected. The skin and mucous membranes become dry.

Eye: Effects of atropine on eye are depicted as follows (also see Table 2.6 ):

Effects on eye last for 7–10 days following topical administration of atropine.

Table 2.6 ■

Effects of atropine and phenylephrine/ephedrine on eye

Atropine	Phenylephrine/ephedrine
1. It is an anticholinergic agent – causes passive mydriasis	1. It is a sympathomimetic agent – causes active mydriasis due to contraction of radial muscle fibres of the iris
2. There is loss of accommodation (it is cycloplegic), photophobia and blurring of vision; cycloplegia is due to paralysis of ciliary muscle; the lens becomes flat and vision is fixed for distant objects.	2. It does not cause cycloplegia
3. There is loss of light reflex	3. There is no loss of light reflex
4. IOP may rise and acute congestive glaucoma may be precipitated in person with shallow anterior chamber; it causes mydriasis and relaxation of ciliary muscle which occlude the canal of Schlemm, resulting in obstruction to the flow of aqueous humour	4. IOP is reduced due to a decrease in the formation of aqueous humour

5.
Smooth muscles:
- (a)
  GIT: Atropine decreases tone and motility of the gut, but increases sphincter tone and may cause constipation. It also relaxes smooth muscle of the gall bladder.
- (b)
  Urinary bladder: Atropine relaxes detrusor muscle of the bladder, but increases the tone of trigone and sphincter – may cause urinary retention, especially in elderly men with enlarged prostate.
- (c)
  Bronchi: Atropine relaxes the bronchial smooth muscle. It also reduces secretion and mucociliary clearance resulting in mucus plug that may block the airway.

Pharmacokinetics.

Atropine, scopolamine and most of the synthetic tertiary amines are well absorbed from the conjunctiva and GI tract; are widely distributed all over the body; cross BBB; partly metabolized in liver and partly excreted unchanged in urine.

Atropine substitutes: Atropine acts on all subtypes of muscarinic receptors.

Atropine substitutes have selective or relatively selective action on a particular organ, hence produce less adverse effects than atropine .

1.
Atropine substitutes used in the eye
- (a)
  Homatropine
  - ■
    Semisynthetic atropine derivative
  - ■
    Less potent than atropine
  - ■
    Duration of action (mydriasis and cycloplegia) is 1–3 days
- (b)
  Cyclopentolate and tropicamide
  - ■
    Synthetic atropine derivatives with rapid onset (tropicamide is the fastest acting) and shorter duration of action than atropine.
  - ■
    Action of cyclopentolate lasts for 24 hours; tropicamide is the shortest acting and action lasts for 6 hours.
2.
Antispasmodics
- (a)
  Dicyclomine
  - ■
    Tertiary amine
  - ■
    Has antispasmodic and antiemetic properties
  - ■
    Useful in dysmenorrhoea and abdominal colic
- (b)
  Valethamate
  - ■
    Tertiary amine
  - ■
    Has antispasmodic effect
  - ■
    Useful in intestinal and urinary colic
- (c)
  Oxybutynin
  - ■
    Has selective action at M ₁ and M ₃ receptors in urinary bladder and salivary gland.
  - ■
    Has vasicoselective action – useful for relief of spasm after urologic surgeries, for increasing bladder capacity in paraplegics and in nocturnal enuresis.
- (d)
  Tolterodine
  - ■
    More selective for urinary bladder than salivary glands, hence dryness of mouth is less.
  - ■
    Used to decrease frequency and urgency in detrusor overactivity.
- (e)
  Flavoxate
  - ■
    Similar to oxybutynin
  - ■
    Used to relieve urgency and frequency due to cystitis, prostatitis or urethritis
- (f)
  Darifenacin, Solifenacin
  - ■
    Have selective action on urinary bladder (M ₃ ) – useful for relief of spasm after urologic surgeries and urinary incontinence.
  - ■
    Are longer acting than oxybutynin.
  - ■
    Oxybutynin, flavoxate, tolterodine, darifenacin and solifenacin are vasicoselective anticholinergics.
- Drotaverine
  - ■
    Not an anticholinergic agent
  - ■
    Inhibits phosphodiesterase enzyme
  - ■
    Used as antispasmodic for relief of uterine spasm, intestinal and renal colic
3.
Ipratropium bromide and tiotropium bromide
- ■
  Quaternary compounds administered by inhalation route.
- ■
  Have a selective action on bronchial smooth muscle – bronchodilatation (mainly in the larger airways).
- ■
  Do not affect mucociliary clearance.
- ■
  Tiotropium (24 hours) is longer acting than ipratropium (6 hours).
- ■
  Dryness of mouth is the main side effect of these agents.
4.
Pirenzepine
- ■
  Has selective action on gastric acid secretion (M ₁ ) – useful in peptic ulcer.
- ■
  Anticholinergic side effects – dryness of mouth, constipation, tachycardia and urinary retention are rare.
5.
Benzhexol and benztropine
- ■
  They are centrally acting anticholinergic agents used in parkinsonism.
6.
Glycopyrrolate
- ■
  Quaternary compound – central side effects are rare.
- ■
  Used for preanaesthetic medication.
7.
Propantheline
- ■
  Useful in peptic ulcer and as an antispasmodic.
- ■
  Rarely used at present.
8.
Clidinium
- ■
  Quaternary compound
- ■
  Has antisecretory and antispasmodic properties
- ■
  Useful in peptic ulcer and irritable bowel syndrome
9.
Hyoscine butylbromide
- ■
  Quaternary compound; available for oral and parenteral administration.
- ■
  Used as antispasmodic for relief of oesophageal and GI colics.

Therapeutic uses of atropine and its substitutes

1.
Ophthalmic uses:
- ■
  As mydriatic and cycloplegic – for refraction testing. Atropine, homatropine, cyclopentolate or tropicamide are used topically. The action of atropine lasts for 7–10 days. Tropicamide is the preferred mydriatic as it has a short duration of action. In children, atropine is preferred because of its greater efficacy.
- ■
  As mydriatic – for funduscopic examination, short-acting agent is used.
- ■
  In iridocyclitis – atropinic mydriatics are used alternatively with miotics to break or prevent adhesions between iris and lens.
2.
As preanaesthetic medication: Atropine or glycopyrrolate is used. They are used prior to the administration of general anaesthetics:
- ■
  To prevent vagal bradycardia during anaesthesia.
- ■
  To prevent laryngospasm by decreasing respiratory secretions.
  - Glycopyrrolate is a quaternary ammonium compound and has only peripheral anticholinergic effects.
3.
Sialorrhoea: Synthetic derivatives (glycopyrrolate) are used to decrease excessive salivary secretion, e.g. in heavy metal poisoning and parkinsonism.
4.
Chronic obstructive pulmonary disease (COPD) and bronchial asthma: Ipratropium bromide and tiotropium bromide are used in COPD and bronchial asthma. They are administered by metered dose inhaler or nebulizer. They produce bronchodilatation without affecting mucociliary clearance, hence are preferred to atropine.
5.
Anticholinergics are useful as antispasmodic in dysmenorrhoea, intestinal and renal colic. They are less effective in biliary colic.
6.
Urinary disorders: Oxybutynin and flavoxate have more prominent effect on bladder smooth muscle, hence are used to relieve spasm after urologic surgery. Tolterodine has selective action on bladder smooth muscle (M ₃ ), hence is used to relieve urinary incontinence.
7.
Poisoning:
- ■
  In OP poisoning, atropine is the life-saving drug (see p. 61).
- ■
  In some types of mushroom poisoning ( Inocybe species), atropine is the drug of choice (see p. 54).
- ■
  Atropine is used in curare poisoning with neostigmine to counteract the muscarinic effects of neostigmine.
8.
As vagolytic: Atropine is used to treat sinus bradycardia and partial heart block due to increased vagal activity. It improves A–V conduction by vagolytic effect.
9.
Parkinsonism: Centrally acting anticholinergic drugs such as benzhexol (trihexyphenidyl), benztropine, biperiden, procyclidine, etc. are the preferred agents for prevention and treatment of drug-induced parkinsonism. They are also useful in idiopathic parkinsonism, but less effective than levodopa. They control tremor and rigidity of parkinsonism.

Adverse effects and contraindications.

The adverse effects of atropine are due to the extension of its pharmacological actions.

1.
GIT: Dryness of mouth and throat, difficulty in swallowing, constipation, etc.
2.
Eye: Photophobia, headache, blurring of vision; in elderly persons with shallow anterior chamber, they may precipitate acute congestive glaucoma. Hence, anticholinergics are contraindicated in glaucoma.
3.
Urinary tract: Difficulty in micturition and urinary retention especially in elderly men with enlarged prostate. So, they are contraindicated in these patients.
4.
CNS: Large doses produce restlessness, excitement, delirium and hallucinations.
5.
CVS: Tachycardia, palpitation and hypotension.
6.
Acute belladonna poisoning: It is more common in children. The presenting features include fever, dry and flushed skin, photophobia, blurring of vision, difficulty in micturition, restlessness, excitement, confusion, disorientation and hallucinations.
- Severe poisoning may cause respiratory depression, cardiovascular collapse, convulsions, coma and death.
- Treatment of belladonna poisoning (Atropine poisoning): It is mainly symptomatic.
- 1.
  Hospitalization.
- 2.
  Gastric lavage with tannic acid in case poison was ingested.
- 3.
  Tepid sponging to control hyperpyrexia.
- 4.
  Diazepam to control convulsions.
- 5.
  The antidote for severe atropine poisoning is physostigmine (1–4 mg). It is injected intravenously slowly. It is a tertiary amine – counteracts both peripheral and central effects of atropine poisoning. Hence, physostigmine is preferred to neostigmine.

Scopolamine.

Scopolamine (hyoscine), another belladonna alkaloid, produces all the actions of atropine. In therapeutic doses, it produces prominent CNS depression with sedation and amnesia. Scopolamine has shorter duration of action than atropine. It has more prominent actions on eye and secretory glands. By blocking cholinergic activity, scopolamine suppresses vestibular disturbances and prevents motion sickness ( Fig. 2.15 ). It is the drug of choice for motion sickness – can be administered orally or as a transdermal patch. It is more effective for prevention of motion sickness, hence should be given (0.2 mg oral) at least half an hour before journey. The patch is placed behind the ear over the mastoid process. The patch should be applied at least 4–5 hours before the journey, and its effect lasts 72 hours. Scopolamine causes sedation and dryness of mouth. It can be administered parenterally as a preanaesthetic agent.

Drug interactions of anticholinergics.

H ₁ -blockers, tricyclic antidepressants (TCAs), phenothiazines, etc. have atropine-like action, hence may potentiate anticholinergic side effects.

Atropine alters absorption of some drugs by delaying gastric emptying – the bioavailability of levodopa is reduced, whereas the absorption of tetracyclines and digoxin is enhanced due to increased GI transit time.

Ganglion blockers

They act at N _N receptors of the autonomic ganglia (block both parasympathetic and sympathetic ganglia) and produce widespread complex effects ( Fig. 2.16 ). The ganglion blockers have ‘atropine-like’ action on heart (palpitation and tachycardia), eyes (mydriasis and cycloplegia), GIT (dryness of mouth and constipation), bladder (urinary retention). They decrease sweat secretion and cause impotence in males. Blockade of sympathetic ganglia results in marked postural hypotension.

No selective ganglion blockers are available till now. Hence, they are rarely used in therapy.

Trimethaphan is a short-acting ganglion blocker that must be given by i.v. infusion. At present, the only use of trimethaphan is to produce controlled hypotension during neurosurgery.

Nicotine is obtained from tobacco leaves. It has initial stimulating, later a prolonged blocking effect on the autonomic ganglia. Tobacco smoking and chewing is a serious risk factor for oral, lung, heart and other diseases.

Treatment of nicotine addiction

Nicotine chewing gum and transdermal patch: They are useful as nicotine replacement therapy.

Bupropion : It inhibits NA and DA reuptake and is used for smoking cessation.

Varenicline : It is a partial agonist at nicotinic receptors. It decreases craving and withdrawal symptoms during smoking cessation.

Skeletal muscle relaxants PH1.15

Skeletal muscle relaxants decrease skeletal muscle tone by peripheral or central action.

Physiology of skeletal muscle contraction

Classification

Centrally acting skeletal muscle relaxants

Most of the centrally acting skeletal muscle relaxants are available in combination with one or other nonsteroidal anti-inflammatory drugs (NSAIDs). All of them cause certain degree of sedation. They act by depressing polysynaptic pathways in spinal and supraspinal sites. They are used to reduce spasm associated with cerebral palsy, trauma, sprain, tetanus, multiple sclerosis, etc. ( Table 2.7 for characteristics of these drugs).

Table 2.7 ■

Characteristics of centrally acting skeletal muscle relaxants

Drug	Route	Uses	Side effects
^a Baclofen: GABA _B agonist	• Oral	• Spinal cord lesions • Multiple sclerosis • Amyotrophic lateral sclerosis	Drowsiness, dry mouth, diarrhoea, confusion, ataxia, vomiting
Diazepam and other benzodiazepines: GABA _A agonists	• Oral • Parenteral	• Tetanus and other conditions associated with muscle spasm	Sedation, drowsiness
^a Tizanidine: Central α ₂ -agonist	• Oral	• Multiple sclerosis • Spinal cord injury or disease	Drowsiness, dizziness, disorientation, ataxia, headache
Chlorzoxazone, methocarbamol: Act on spinal interneurons	• Oral	• Acute muscle spasm due to trauma	Drowsiness
Riluzole: Inhibits glutamate release	• Oral	• Amyotrophic lateral sclerosis	Diarrhoea
Carisoprodol: Mechanism of action not clearly known	• Oral	• Muscle sprain	Drowsiness
Thiocolchicoside	• Oral	• Sprain, muscle spasm due to trauma	Diarrhoea, drowsiness, rashes

Block release of excitatory transmitter in the spinal cord → depresses polysynaptic reflexes.

Neuromuscular blockers

Unlike centrally acting skeletal muscle relaxants, these drugs interfere with neuromuscular transmission, do not affect CNS and are administered intravenously. Neuromuscular blockers include nondepolarizing (competitive) and depolarizing blockers.

Depolarizing blockers: Succinylcholine (suxamethonium).

Succinylcholine (SCh) is a quaternary ammonium compound. The structure resembles two molecules of ACh linked together. It acts as a partial agonist at N _M receptors, hence causes initial fasciculations and later flaccid paralysis due to prolonged depolarization (phase I block). With continued exposure to the drug, the membrane becomes desensitized that leads to phase II block, which resembles the nondepolarizing block and is partially reversed by anticholinesterases. Phase II block can occur in patients with atypical pseudocholinesterase.

SCh is rapidly hydrolysed by pseudocholinesterase, hence has a very short duration of action (3–8 minutes). Transient apnoea is usually seen at the peak of its action. In people with liver disease or atypical pseudocholinesterase due to genetic defect, the metabolism of SCh becomes slow which results in severe neuromuscular blockade leading to respiratory paralysis with prolonged apnoea. This is referred to as ‘ prolonged succinylcholine apnoea’ . There is no antidote available, therefore:

■
Fresh frozen plasma should be infused.
■
Patient should be ventilated artificially until full recovery.

Adverse effects

1.
Muscle pain is due to initial fasciculations (muscle soreness).
2.
Increased IOP due to contraction of external ocular muscles and it lasts for few minutes.
3.
Aspiration of gastric contents may occur due to increased intragastric pressure.
4.
Hyperkalaemia – fasciculations release K ⁺ into the blood.
5.
Sinus bradycardia is due to vagal stimulation.
6.
SCh apnoea (prolonged apnoea).
7.
Malignant hyperthermia especially when used with halothane in genetically susceptible individuals. This is treated with intravenous dantrolene, rapid cooling, inhalation of 100% oxygen and control of acidosis.

Competitive blockers (nondepolarizing blockers; table 2.8 ).

Claude Bernard showed experimentally the site of action of curare. Curare is a mixture of alkaloids and was used as an arrow poison. Among them, d-TC is the most important alkaloid which has N _M blocking activity. d-TC is the prototype drug of competitive blockers.

Table 2.8 ■

Features of nondepolarizing (competitive) blockers

Nondepolarizing blockers
1. d-TC: An alkaloid obtained from Chondrodendron tomentosum • Prototype competitive N _M blocker • Causes flaccid paralysis • Causes histamine release, ganglionic blockade • Has long duration of action
2. Pancuronium • Synthetic agent • Produces competitive blockade • Has long duration of action • Minimal/no histamine release • Has vagolytic action, hence causes tachycardia
3. Pipecuronium • Has long duration of action • May cause bradycardia and hypotension
4. Doxacurium • Minimal histamine release • Has long duration of action
5. Vecuronium • One of the commonly used neuromuscular blocker • Has intermediate duration of action • Minimal/no tendency to release histamine or cause cardiovascular effects • Does not cross placental barrier
6. Rocuronium • Has intermediate duration of action • Minimal/no tendency to release histamine • Has a rapid onset of action
7. Atracurium • Has intermediate duration of action • Undergoes spontaneous degradation in plasma (Hofmann degradation) in addition to destruction by cholinesterases • Causes histamine release • Safe in patients with hepatic and renal dysfunction
8. Cisatracurium • Has intermediate duration of action • More potent than atracurium • Does not cause histamine release • Undergoes spontaneous degradation in plasma (Hofmann degradation) • Safe in elderly and patients with hepatic and renal dysfunction
9. Mivacurium • Has short duration of action (15–20 minutes) • Rapidly inactivated by plasma cholinesterases • Does not require reversal • Causes histamine release • Duration of action is prolonged in patients with pseudocholinesterase deficiency

Mechanism of action.

ACh is the agonist, whereas d-TC is the antagonist at N _M receptors. Curariform drugs competitively antagonize the actions of ACh at the N _M receptors of the NMJ. Anticholinesterases (neostigmine or edrophonium) are used to reverse the effects of competitive blockers by increasing the concentration of ACh.

Actions.

Competitive blockers produce flaccid paralysis. The order of muscles affected is extrinsic eye muscles–neck (muscles of phonation and swallowing)–face–hands–feet–limbs–trunk and finally, the respiratory muscles (intercostal muscles and diaphragm). But recovery occurs in reverse order – the respiratory muscles are the first to recover. Consciousness and appreciation of pain are not affected.

■
d-TC, mivacurium and atracurium cause histamine release which can manifest as hypotension, bronchospasm, etc.
■
Pancuronium, vecuronium, doxacurium and rocuronium have minimal/no tendency to cause histamine release.
■
Vecuronium, doxacurium and rocuronium have minimal tendency to cause cardiovascular effects like hypotension, cardiovascular collapse, etc. These effects are also less marked with pancuronium and pipecuronium. Cardiovascular side effects are prominent with d-TC and mivacurium.
■
Among competitive neuromuscular blockers, rocuronium has a rapid onset of action; hence, it can be used for endotracheal intubation.

■

Comparative features of d-TC and SCh are shown in Table 2.9 .

Table 2.9 ■

Comparative features of d-TC and succinylcholine

d-TC	Succinylcholine
1. Natural alkaloid	1. Synthetic
2. Nondepolarizing blocker	2. Depolarizing blocker
3. Long acting (80 minutes)	3. Rapidly metabolized by pseudocholinesterase, hence short acting (3–8 minutes)
4. Causes flaccid paralysis	4. Initially causes fasciculations and later flaccid paralysis
5. Causes histamine release (+++)	5. Causes histamine release (++)
6. Neostigmine reverses the block	6. Phase II block, which resembles nondepolarizing block is partially reversed by neostigmine
7. Uses: As adjuvant to general anaesthesia	7. Succinylcholine is preferred for short procedures, e.g. diagnostic endoscopies, endotracheal intubation and orthopaedic manipulations
8. Adverse effects (see p. 73)	8. Adverse effects (see p. 71)

Pharmacokinetics.

Neuromuscular blockers are quaternary ammonium compounds. They are highly ionized, hence poorly absorbed from GI tract. They are administered intravenously. They are mainly confined to ECF space; do not cross placental and blood–brain barrier. They are metabolized in liver and some are excreted unchanged in urine.

Adverse effects.

The adverse effects of nondepolarizing drugs are hypotension, respiratory paralysis, bronchospasm and aspiration of gastric contents.

Drug interactions of skeletal muscle relaxants

1.
Nondepolarizing blockers × antibiotics
- Aminoglycosides inhibit the release of ACh from motor nerve and potentiate the effect of nondepolarizing blockers, hence require dose reduction in patients treated with aminoglycosides. Tetracyclines and clindamycin also potentiate the effect of nondepolarizing blockers.
2.
Thiazides/loop diuretics × nondepolarizing blockers
- Hypokalaemia caused by thiazides/loop diuretics may potentiate the effect of nondepolarizing blockers.
3.
SCh × thiopentone
- These drugs are chemically incompatible (in vitro; pharmaceutical interaction) hence result in precipitation when mixed in the same syringe.
4.
General anaesthetics × nondepolarizing blockers
- Ether has curarimimetic effect on skeletal muscle, hence enhances the effect of nondepolarizing blockers. Fluorinated anaesthetics (isoflurane, desflurane and sevoflurane) also produce similar effect but to a lesser extent.

Factors affecting action of neuromuscular blockers

1.
pH changes: Metabolic acidosis and respiratory acidosis increase the duration of block.
2.
Hypothermia: It potentiates neuromuscular block by delaying the metabolism and elimination of these drugs.
3.
Myasthenia gravis: Myasthenic patients are highly sensitive to competitive neuromuscular blockers.
4.
Aminoglycoside antibiotics: They potentiate the effect of both competitive and nondepolarizing blockers by inhibiting presynaptic release of ACh.
5.
Inhalational anaesthetics: Anaesthetics like halothane, isoflurane and ketamine increase the effects of neuromuscular blocking agents.

Uses

1.
The main use of neuromuscular blockers is as adjuvant to general anaesthetics for producing satisfactory skeletal muscle relaxation during surgical procedures in abdomen and thorax, orthopaedics, etc. SCh is preferred for short procedures, e.g. diagnostic endoscopies, endotracheal intubation and orthopaedic manipulations. Vecuronium is commonly used in routine surgeries. Pancuronium and pipecuronium are used in surgeries of long duration.
2.
SCh /mivacurium is used during electroconvulsive therapy (ECT) to prevent trauma due to convulsions.
3.
For tetanus and status epilepticus when not controlled by other drugs, competitive neuromuscular blockers can be used.
4.
Competitive neuromuscular blockers, e.g. vecuronium, can be used for ventilatory support in critically ill patients.

Reversal of neuromuscular blockade.

Edrophonium or neostigmine by increasing the concentration of ACh reverses the effect of d-TC and other competitive blockers at NMJ. Use of prior atropine administration is necessary to block the muscarinic effects of anticholinesterases ( Fig. 2.17 ). Mivacurium (short acting), atracurium (intermediate acting), etc. do not require reversal.

Sugammadex.

It is administered intravenously for rapid reversal of neuromuscular blocking action of rocuronium and vecuronium. It encapsulates the drugs, thus preventing their action.

Directly acting skeletal muscle relaxant: Dantrolene.

Dantrolene is a directly acting skeletal muscle relaxant. It inhibits depolarization-induced Ca ²⁺ release (by blocking ryanodine receptors) from sarcoplasmic reticulum and produces skeletal muscle relaxation. Intravenous dantrolene is the life-saving drug in malignant hyperthermia. It is used orally to reduce spasm in multiple sclerosis, cerebral palsy, spinal injuries, etc. The side effects are drowsiness, diarrhoea, dizziness, headache, fatigue and rarely hepatotoxicity.

Botulinum toxin A.

It is obtained from Clostridium botulinum , a gram-positive anaerobic bacterium. The toxin prevents release of ACh into the synaptic cleft by inhibiting proteins necessary for the release of ACh. Thus, it normalizes the tone in hyperreactive or spastic muscles when given locally. It is given intradermally for antiwrinkle effect in cosmetic procedures and into the muscle in multiple doses for spasticity or dystonia. Botulinum toxin A is injected under ultrasound guidance into salivary glands in sialorrhoea and drooling. Adverse effects are pain at the site of injection, muscle paralysis, myalgia and occasionally rashes.

Adrenergic agonists (sympathomimetic agents) PH1.13

Adrenergic agonists mimic the actions of sympathetic stimulation.

Adrenergic transmission

The transmitter in the sympathetic system is noradrenaline (NA; norepinephrine). Nerves that synthesize, store and release NA are called adrenergic (sympathetic) nerves.

Synthesis of catecholamines begins with the amino acid tyrosine, which is transported into the adrenergic neuron by active transport. In the neuronal cytosol, tyrosine is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase and DOPA to dopamine (DA) by dopa decarboxylase. DA enters storage vesicles of the nerve terminal by active transport, where it is converted to NA by the enzyme dopamine β-hydroxylase (this enzyme is present only in the storage vesicles); NA formed gets stored in the vesicles. In the adrenal medulla, NA is further converted to adrenaline by N -methyltransferase. Small quantities of NA are released continuously into the synaptic cleft and large quantities during nerve stimulation ( Fig. 2.18 ).

Table 2.10 ■

Drugs affecting adrenergic transmission and their uses

Drug	Action	Response/therapeutic uses
Metyrosine (α-Methyltyrosine)	Inhibits tyrosine hydroxylase enzyme	Blocks synthesis of NA – useful in the treatment of selected cases of pheochromocytoma
α-Methyldopa	Replacement of NA by false transmitter (α-Methyl-NA: central α ₂ -agonist)	Decreases central sympathetic outflow; α-Methyl NA is an α ₂ -agonist, used in hypertension especially in pregnancy
Reserpine	Blocks vesicular uptake and storage of NA	Depletion of NA; degradation by mitochondrial MAO; was used in hypertension
Bretylium, guanadrel	Prevent the release of NA	Ventricular fibrillation
Cocaine, tricyclic antidepressants (TCAs)	Inhibit neuronal reuptake of NA (uptake-1)	Accumulation of NA at receptors
Adrenergic agonists	Mimic the effects of neurotransmitter at receptor	Sympathomimetic effects
Tyramine, ephedrine, amphetamine	Promote the release of NA from adrenergic nerve terminals	Tyramine, amphetamine (indirectly acting) and ephedrine (mixed acting) sympathomimetics
Adrenergic antagonists	Block the effects of neurotransmitter at receptors	For uses: See pp. 90–91; 94–95.
Tranylcypromine (nonselective MAO inhibitor)	Potentiates tyramine action	As antidepressant
Selegiline (selective MAO-B inhibitor)	Inhibits degradation of DA in the brain	Increases DA level in the brain, adjunct in parkinsonism
Entacapone (peripheral COMT inhibitor)	Inhibits degradation of DA	Adjunct in parkinsonism
Tolcapone (peripheral and central COMT inhibitor)	Inhibits degradation of DA	Adjunct in parkinsonism

Three processes are involved in termination of action of released NA in the synaptic cleft (fate of released NA in the synaptic cleft):

1.
Most of the released NA is taken back into adrenergic nerve terminals (neuronal reuptake), which is either stored in vesicles or inactivated by mitochondrial monoamine oxidase (MAO) in the cytosol. Neuronal reuptake is the most important mechanism through which termination of action of NA takes place in the synaptic cleft.
2.
Small amount of NA from the synaptic cleft diffuses into circulation and gets inactivated in liver by catechol- O -methyltransferase (COMT) and MAO.
3.
Small quantity of NA is transported into other tissues (extraneuronal uptake).

Metabolism of catecholamines

Vanillylmandelic acid (VMA) is the main metabolite of catecholamines excreted in urine. Normal value of VMA is 4–8 mg per 24 hours urine. Its levels are raised in pheochromocytoma, a tumour of adrenal medulla and sympathetic ganglia. Estimation of the levels of catecholamines and their metabolites in blood and urine is of great value in the diagnosis of pheochromocytoma. CT (computed tomography) and MRI (magnetic resonance imaging) scan are the important diagnostic aids.

Types, distribution and functions of adrenergic receptors

Ahlquist divided adrenergic receptors into α and β types, which are located on the cell membrane. All adrenergic receptors are G-protein coupled receptors and regulate the production of intracellular second messengers; increase in IP ₃ /DAG (α ₁ ), ↓cAMP (α ₂ )and ↑cAMP (β). They are further divided into various subtypes, which are as follows:

Distribution of various adrenergic receptors is indicated in Fig. 2.19 .

1.
Effect of activation of α ₁ -receptors
- ■
  Blood vessels: Constriction
- ■
  GI sphincter (anal): Increase in tone
- ■
  Urinary sphincter: Increase in tone
- ■
  Radial muscle (iris): Contraction (mydriasis)
2.
Effect of activation of presynaptic α ₂ -receptors
- ■
  Mediate negative feedback control on NA secretion (i.e. stimulation of α ₂ -receptors decreases release of NA from sympathetic nerve endings)
3.
Effect of activation of postsynaptic vascular α ₂ -receptors
- ■
  Mediate stimulatory effects: Vasoconstriction and venoconstriction
4.
Effect of activation of α ₂ -receptors on various secretions
- ■
  Beta cells of islets of Langerhans in pancreas: Decrease in insulin secretion
- ■
  Ciliary epithelium: Reduction of aqueous humour secretion
- ■
  Sympathetic nerve endings: Decrease in NA release
5.
Effect of activation of β ₁ -receptors
- ■
  Heart: Cardiac stimulation
- ■
  Kidney: Promote renin release
6.
Stimulatory effects due to activation of β ₂ -receptors
- ■
  Liver: Stimulation of glycogenolysis
- ■
  Skeletal muscle: Contraction
- ■
  Ciliary epithelium: Increase in secretion of aqueous humour
- ■
  Uptake of K ⁺ into cells
7.
Inhibitory effects due to activation of β ₂ -receptors
- ■
  Bronchial, uterine (pregnant), vascular and bladder smooth muscles: Relaxation
- ■
  In GI smooth muscle, activation of both α- and β-receptors causes relaxation
8.
Effect of activation of β ₃ -receptors
- ■
  Adipose tissue: Lipolysis

Adrenergic drugs (sympathomimetics)

The sympathomimetic drugs mimic effects of sympathetic stimulation ( Fig. 2.20 ). They are also referred to as adrenergic agonists.

Classification of adrenergic drugs (sympathomimetics)

1.
On the basis of their chemical structure
- (a)
  Catecholamines: Sympathomimetics with catechol nucleus (3,4-dihydroxy benzene) are called catecholamines, e.g. adrenaline, noradrenaline, DA, isoprenaline and dobutamine.
- (b)
  Noncatecholamines: Sympathomimetics that lack catechol nucleus are called noncatecholamines, e.g. tyramine, ephedrine, amphetamine, phenylephrine and salbutamol.

On the basis of their mechanism of action ( Table 2.11 ):

(a)
Direct acting: They act directly by stimulating adrenergic receptors.
(b)
Indirect acting: They act by releasing noradrenaline from adrenergic nerve endings.
(c)
Mixed acting: These drugs act both directly and indirectly.

Table 2.11 ■

Summary of sympathomimetic agents

Adrenergic agonists	Receptor action	Therapeutic uses
1. Directly acting
• Adrenaline	α ₁ -, α ₂ -, β ₁ -, β ₂ - and β ₃ -agonist	A naphylactic shock, C ardiac arrest, to prolong D uration of local anaesthesia, to control E pistaxis and other capillary oozing, B ronchial asthma (acute) (ABCDE)
• Noradrenaline	α ₁ -, α ₂ - and β ₁ -agonist	Hypotensive states
• Isoprenaline	β ₁ - and β ₂ -agonist	Heart block, cardiac arrest
• Dobutamine	Relatively selective β ₁ -agonist	Cardiogenic shock due to acute myocardial infarction (MI), congestive cardiac failure (CCF) or cardiac surgery
• Salbutamol (Albuterol) • Levalbuterol • Pirbuterol • Terbutaline • Salmeterol • Formoterol	Selective β ₂ -agonists	Bronchial asthma, to suppress premature labour (as uterine relaxant)
• Ritodrine • Isoxsuprine	Selective β ₂ -agonists; main action on uterus	Uterine relaxants
• Phenylephrine • Methoxamine	Selective α ₁ -agonists	Vasopressor agents, nasal decongestants, as mydriatic (phenylephrine), allergic or vasomotor rhinitis
• Naphazoline • Oxymetazoline • Xylometazoline	α ₁ + α ₂ -agonists	Nasal decongestants (α ₁ stimulation); structural damage can occur due to intense vasoconstriction (α ₂ stimulation)
• Clonidine, α-Methyldopa	α ₂ -agonists	Hypertension
• Apraclonidine • Brimonidine	α ₂ -agonists	Glaucoma (topical)
2. Indirectly acting
• Amphetamine • Methamphetamine • Methylphenidate	They act by releasing NA in the periphery; NA, DA and 5-hydroxytryptamine (5-HT) centrally	Narcolepsy, attention-deficit hyperactivity disorder (ADHD)
3. Mixed acting
• Ephedrine	α ₁ , α ₂ , β ₁ and β ₂ (direct action) + releases NA (indirect action)	Intravenous ephedrine is used for the treatment of hypotension due to spinal anaesthesia
• Dopamine	α ₁ , α ₂ , β ₁ and D ₁ + releases NA	Cardiogenic shock, CCF with oliguria
• Mephentermine	α ₁ -agonist + releases NA	Hypotensive states

3.
On the basis of their therapeutic use:
- (a)
  To raise BP in shock: DA, noradrenaline, ephedrine, phenylephrine, methoxamine, mephentermine.
- (b)
  As bronchodilator: Salbutamol, levalbuterol, pirbuterol, terbutaline, bambuterol, salmeterol, formoterol.
- (c)
  As cardiac stimulant: Adrenaline, isoprenaline, dobutamine.
- (d)
  As CNS stimulant: Amphetamine, dextroamphetamine, methamphetamine.
- (e)
  As nasal decongestant: Phenylephrine, xylometazoline, pseudoephedrine, oxymetazoline, naphazoline.
- (f)
  As anorexiant: Dextroamphetamine, mazindol, phentermine, sibutramine.
- (g)
  As uterine relaxant: Isoxsuprine, terbutaline, salbutamol, ritodrine.

Direct-acting sympathomimetics

Adrenaline (epinephrine): α _1- , α _2- , β _1- , β _2- and β ₃ -agonist.

It is a catecholamine, which is secreted mainly by adrenal medulla. Adrenaline is a direct-acting, nonselective adrenergic agonist.

Pharmacological actions.

Adrenaline acts on α _1- , α _2- , β _1- , β _2- and β ₃ -receptors.

1.
Cardiovascular system
- (a)
  Heart: Adrenaline is a powerful cardiac stimulant. It acts mainly by interacting with β ₁ -receptors and produces various effects. They are as follows:
  - ■
    Increase in heart rate – ↑ rate of spontaneous depolarization in SA node (positive chronotropic effect)
  - ■
    Increase in myocardial contractility (positive inotropic effect)
  - ■
    Increase in conduction velocity (positive dromotropic effect)
  - ■
    Increase in cardiac output
  - ■
    Increase in automaticity
  - ■
    Cardiac work and its oxygen requirement is markedly increased
  - ■
    Increase in the excitability and tendency to cause cardiac arrhythmias
- (b)
  Blood vessels and BP: Blood vessels of the skin and mucous membranes (α ₁ -receptors) are constricted by adrenaline. It also constricts renal, mesenteric, pulmonary and splanchnic vessels, but dilates blood vessels of skeletal muscle and coronary vessels (β ₂ ). Intravenous administration of adrenaline in moderate doses produces biphasic effect. There is an initial rise in BP due to α ₁ (blood vessels) and β ₁ (heart) actions, followed by a fall in BP due to β ₂ -mediated dilatation of blood vessels in skeletal muscle. Administration of adrenaline after α-blocker produces only a fall in BP (β ₂ -action). This is referred to as vasomotor reversal of Dale ( Fig. 2.21 ).
  - If adrenaline is rapidly injected intravenously, there is an increase in both systolic and diastolic BP.
  Fig. 2.21
  Biphasic effect of adrenaline (Adr) on BP and Dale’s vasomotor reversal.
2.
Respiratory system: Adrenaline rapidly relaxes (β ₂ ) bronchial smooth muscle. It is a potent bronchodilator but has a short duration of action. It inhibits the release of inflammatory mediators from mast cells (β ₂ ). It also reduces secretions and relieves mucosal congestion by vasoconstrictor effect (α ₁ ).
3.
GIT: It relaxes the smooth muscle of the gut (α and β ₂ ). It reduces the intestinal tone and peristaltic movements but the effects are transient.
4.
Bladder: It relaxes the detrusor muscle (β ₂ ) and contracts the sphincter (α ₁ ). As a result, it may cause difficulty in urination.
5.
CNS: In therapeutic doses, adrenaline does not cross BBB; hence, CNS effects are minimal. But in high doses, it may cause headache, restlessness and tremor.
6.
Eye: Adrenaline has poor penetration through cornea when applied topically into the eye. Hence, it is administered as a prodrug (see p. 59).
7.
Metabolic effects:
- ■
  Adrenaline increases blood glucose level by:
  - (i)
    Stimulating hepatic glycogenolysis (β ₂ ), which is the predominant effect.
  - (ii)
    Reducing insulin secretion through α ₂ -action.
  - (iii)
    Decreasing uptake of glucose by peripheral tissues.
- ■
  It increases blood lactic acid level by stimulating glycogenolysis in skeletal muscles.
8.
Other effects
- ■
  Adrenaline facilitates neuromuscular transmission and postpones fatigue.
- ■
  It reduces plasma K ⁺ levels by promoting uptake of K ⁺ into cells, particularly into the skeletal muscle (β ₂ ).

Pharmacokinetics.

Adrenaline is not suitable for oral administration because of its rapid inactivation in the GI mucosa and liver. Adrenaline can be given subcutaneously. In anaphylactic shock, absorption of s.c. adrenaline is poor; hence, it is given intramuscularly. In cardiac arrest, it is given intravenously. It does not cross BBB; is rapidly metabolized by COMT and MAO, and the metabolites are excreted in urine.

Adverse effects and contraindications.

The adverse effects of adrenaline are an extension of its pharmacological actions. They are tachycardia, palpitation, headache, restlessness, tremors and rise in BP. The serious side effects are cerebral haemorrhage and cardiac arrhythmias. In high concentration, adrenaline may cause acute pulmonary oedema due to shift of blood from systemic to pulmonary circulation. Adrenaline is contraindicated in most of the cardiovascular diseases such as hypertension, angina, cardiac arrhythmias and congestive cardiac failure (CCF). In patients on β-blockers, it may cause hypertensive crisis and cerebral haemorrhage due to unopposed action on vascular α ₁ -receptors.

Therapeutic uses of adrenaline (ABCDE)

1.
A naphylactic shock: Adrenaline is the life-saving drug in anaphylactic shock. Adrenaline 0.3–0.5 mL of 1:1000 solution (1 mg/mL) is administered intramuscularly. It rapidly reverses the manifestations of severe allergic reactions. The beneficial effect of adrenaline in anaphylactic shock is shown below. Adrenaline produces the following effects:
2.
C ardiac resuscitation: In the treatment of cardiac arrest due to drowning or electrocution, adrenaline is injected intravenously in 1:10,000 (0.1 mg/mL) concentration along with other supportive measures such as external cardiac massage.
3.
Prolongs the D uration of local anaesthesia: Adrenaline (1:100,000) with lignocaine. Adrenaline, by its vasoconstrictor effect (α ₁ ) delays absorption of the local anaesthetic and prolongs the duration of local anaesthesia.
4.
Controls E pistaxis and other capillary oozing: Adrenaline is used as a local haemostatic to control bleeding following tooth extraction and during surgical procedures in nose, throat, larynx, etc. because of its vasoconstrictor effect.
5.
Glaucoma: Adrenaline has poor penetration when applied locally into the eye; hence, it is administered as a prodrug, dipivefrin (p. 59).
6.
B ronchial asthma: Adrenaline is a powerful bronchodilator and has rapid onset but short duration of action. It is rarely used for acute asthma. Its use has declined because of its dangerous cardiac stimulant effect. The beneficial effects of adrenaline in bronchial asthma are shown in Fig. 2.22 . Adrenaline 0.3–0.5 mL of 1:1000 solution is given subcutaneously. It can be given by nebulization (as inhalation).
Fig. 2.22
Effects of adrenaline in bronchial asthma. LTs, leukotrienes; PGF ₂ α, prostaglandin F ₂ α; PAF, platelet-activating factor.

Noradrenaline: α ₁ -, α ₂ - and β ₁ -agonist.

Noradrenaline is a catecholamine. It is the neurotransmitter in adrenergic system. It acts on α ₁ -, α ₂ - and β ₁ -adrenergic receptors and has negligible β ₂ -action. The main action of NA is on CVS. It has a direct cardiac stimulant effect (β ₁ ), constricts all the blood vessels (α ₁ ) including those of skin, mucous membrane, renal, mesenteric, pulmonary, skeletal muscle, etc. The systolic, diastolic and pulse pressure are increased. There is reflex bradycardia. Noradrenaline, like adrenaline, is not effective orally. It is not suitable for s.c., i.m. or direct i.v. injection because of necrosis and sloughing of the tissues at the site of injection. It is administered by i.v. infusion. It can be used to raise BP in hypotensive states but it may decrease blood flow to vital organs by causing widespread vasoconstriction.

Isoprenaline (isoproterenol): β ₁ -β ₂ and β ₃ -agonist.

It is a synthetic, nonselective β-receptor agonist with a catechol nucleus. It has potent β-actions but no action at α-receptors. Isoprenaline is a powerful cardiac stimulant. It has positive inotropic, chronotropic and dromotropic effects. It dilates renal, mesenteric and skeletal muscle blood vessels. Systolic BP is minimally changed but the diastolic and mean arterial pressure are reduced. It relaxes bronchial and GI smooth muscles. Isoprenaline is not effective orally because of extensive first-pass metabolism. It can be given parenterally or as an aerosol. It is metabolized by COMT. Isoprenaline is used to increase the heart rate in heart block. Side effects are tachycardia, palpitation, cardiac arrhythmias, etc. due to its powerful cardiac stimulant effect.

Dobutamine: Relatively selective β ₁ -agonist.

Dobutamine, a synthetic catecholamine, structurally resembles DA. It acts on β ₁ -, β ₂ - and α ₁ -receptors. It does not act on dopaminergic (D ₁ and D ₂ ) receptors. It is a potent inotropic agent but causes only slight increase in heart rate. Total peripheral resistance is not significantly affected. This is because vasoconstriction (α ₁ -mediated) is balanced by vasodilatation (β ₂ -mediated). It is administered by i.v. infusion in patients with acute heart failure. The side effects are tachycardia (at high doses), rise in BP and tolerance, which can be avoided by intermittent therapy.

Salbutamol, terbutaline, salmeterol, formoterol: Selective β ₂ -adrenergic agonists.

Selective β ₂ -agonists are the main drugs used in bronchial asthma, e.g. salbutamol, levalbuterol, pirbuterol, terbutaline, salmeterol and formoterol. Nonselective β-agonist like adrenaline is rarely used because of its cardiac side effects.

Pharmacological actions.

Pharmacological actions of selective β ₂ -agonists are depicted in Fig. 2.23 . They cause bronchodilatation, relaxation of pregnant uterus, dilatation of blood vessels supplying the skeletal muscle, promote hepatic glycogenolysis and uptake of K ⁺ into cells.

Therapeutic uses

1.
Bronchial asthma: Selective β ₂ -agonists are usually administered by aerosol. They produce prompt bronchodilatation (salbutamol, terbutaline and formoterol) with minimal systemic side effects.
2.
Premature labour: On oral or parenteral administration, salbutamol and terbutaline relax pregnant uterus by interacting with β ₂ -receptors, hence are used to delay premature labour.
3.
Hyperkalaemia: Selective β ₂ -agonists are useful in hyperkalaemia as they promote uptake of K ⁺ into cells, especially into skeletal muscles.

Isoxsuprine.

It relaxes smooth muscles of uterus and blood vessel by acting on β ₂ -receptors. It can be used in dysmenorrhoea, threatened abortion and to delay premature labour. It is available for oral, i.m. and i.v. administration.

Ritodrine: Selective β ₂ -agonist with main action on uterus.

Ritodrine is a β ₂ -agonist with selective action on uterus. It is used as a uterine relaxant to suppress premature labour.

Adverse effects of selective β ₂ -agonists

1.
Tremor is due to stimulation of β ₂ -receptors of skeletal muscle. Tolerance develops to this effect on continued administration.
2.
Tachycardia and palpitation are due to stimulation of β ₁ -receptors of heart (β ₂ -selectivity is not absolute – may cause cardiac side effects).
3.
Hyperglycaemia may occur in diabetes patients following parenteral administration of β ₂ -agonists.
4.
Hypokalaemia is due to shift of K ⁺ into cells.

Phenylephrine, methoxamine, mephentermine: Selective α ₁ -adrenergic agonists

Like ephedrine, mephentermine also has cardiac stimulant effect. They are used parenterally to raise the BP in hypotensive states. Phenylephrine is also used topically as a mydriatic and as a nasal decongestant.

Nasal decongestants.

The commonly used α-agonists as nasal decongestants are naphazoline, oxymetazoline and xylometazoline (topical); pseudoephedrine (oral) and phenylephrine (oral and topical). They are used in allergic rhinitis, common cold, sinusitis, etc. These drugs stimulate α-receptors and cause vasoconstriction in the nasal mucous membrane, thus relieve nasal congestion. On prolonged use, they cause rebound congestion (after congestion). Atrophic rhinitis, anosmia and local irritation are the other adverse effects seen with topical decongestants. If systemically absorbed, these drugs may aggravate hypertension.

Pseudoephedrine and phenylephrine are the commonly used oral preparations. These drugs cause less rebound phenomenon, but systemic side effects like hypertension and CNS stimulation are common. They should not be combined with MAO inhibitors because of risk of hypertensive crisis, which could be fatal. Phenylpropanolamine was used as a nasal decongestant. It has been banned because of increased incidence of stroke.

Selective α ₂ -adrenergic agonists.

They include clonidine, α-methyldopa (see p. 106–107) and tizanidine (see p. 70, Table 2.7 ).

Apraclonidine and brimonidine, selective α ₂ -agonists, are used topically in glaucoma (see p. 59).

Indirect-acting sympathomimetic agents

Amphetamine.

Amphetamine is an indirectly acting sympathomimetic agent and has a potent CNS stimulant effect. It occurs in two isomers. The d -isomer has more potent CNS effects and l -isomer on CVS.

Pharmacological actions

Adverse effects.

Adverse effects are due to the extension of its pharmacological actions. They are restlessness, insomnia, confusion, fatigue, tremor, hallucinations and suicidal tendencies. The cardiac side effects are tachycardia, palpitation, hypertension, angina and cardiac arrhythmias.

Treatment of acute intoxication

1.
Acidification of urine with ascorbic acid (vitamin C) promotes the excretion of amphetamine, which is a basic drug.
2.
Sedatives are effective to control CNS symptoms and sodium nitroprusside for hypertension.

Uses

1.
Narcolepsy: It is a sleep disorder characterized by recurrent episodes of uncontrollable desire for sleep. Amphetamine improves narcolepsy by its CNS stimulant effect.
2.
As an anorexiant: Amphetamine-like drugs reduce body weight by suppressing hypothalamic feeding centre. Tolerance to this effect develops rapidly.
3.
Attention-deficit hyperactivity disorder: Amphetamine acts paradoxically and controls the activity in children with hyperactivity disorder. The main adverse effects are loss of appetite and insomnia. Methylphenidate, dextroamphetamine and atomoxetine (selective noradrenaline reuptake inhibitor) are also useful in this disorder.

Modafinil.

It is a CNS stimulant – useful in narcolepsy. Side effects and risk of dependence is lower than amphetamine.

Mixed acting sympathomimetic agents

Ephedrine: α- and β-agonist with na release.

Ephedrine is a mixed acting adrenergic agonist. It is an alkaloid, acts on α _1- , α _2- , β _1- , β ₂ -receptors and releases NA from sympathetic nerve endings.

Pharmacological actions

Uses.

Intravenous ephedrine is the drug of choice to treat hypotension due to spinal anaesthesia as it increases peripheral vascular resistance (PVR), heart rate, cardiac output and thus BP. It was used in heart block, narcolepsy and bronchial asthma. Now, it has been replaced by more selective drugs. The side effects are insomnia, hypertension, tachycardia, palpitation, difficulty in urination; tachyphylaxis occurs on repeated administration.

Dopamine: α ₁₋ , α ₂₋ , β ₁₋ , and D ₁ -agonist with na release.

DA is a catecholamine and the immediate metabolic precursor of NA. It acts on dopaminergic D ₁ receptors as well as β ₁₋ and α ₁ -adrenergic receptors. DA, like adrenaline and noradrenaline, is not effective orally. As DA is rapidly inactivated by COMT and MAO, it is administered by i.v. infusion.

Pharmacological actions.

At low doses (<2 mcg/kg/min), it selectively dilates renal, mesenteric and coronary blood vessels by acting on D ₁ receptors resulting in an increase in GFR and urine output.

At moderate doses (2–5 mcg/kg/min), DA stimulates β ₁ -receptors of heart, increases myocardial contractility and cardiac output, but tachycardia is less prominent. It also stimulates dopaminergic receptors resulting in increase in GFR.

At high doses (>10 mcg/kg/min), it stimulates vascular α ₁ -adrenergic receptors and causes generalized vasoconstriction. This increases afterload and reduces blood flow to renal, mesenteric and other vital organs. So, the beneficial effect seen with low-to-moderate dose of DA is lost at higher doses.

Precautions and adverse effects.

During DA infusion, the dose, BP, heart rate, ECG and urine output should be carefully monitored. The adverse effects seen are mainly due to sympathetic stimulation. They are nausea, vomiting, headache, hypertension, tachycardia, cardiac arrhythmias and angina.

Therapeutic uses

1.
Cardiogenic and septic shock: DA can be used because it increases BP as well as selectively dilates renal, mesenteric, coronary blood vessels and improves blood flow to vital organs.
2.
Severe heart failure with renal impairment: DA improves both cardiac and renal function.

Fenoldopam.

D ₁ agonist: It is administered as i.v. infusion in hypertensive emergencies.

Fenoldopam → D ₁ agonist → Peripheral vasodilatation → ⇩ BP

Its side effects are headache, flushing, reflex tachycardia and rise in intraocular tension.

Anorectics (anorexiants).

Amphetamine-like drugs promote weight loss by acting on hypothalamic feeding centre.

Sibutramine has been banned due to its adverse effects.

Other antiobesity agents

Leptin and rimonabant were used as anorectics. The main adverse effects of these agents are addiction liability, rise in BP, palpitation, sleep disturbances, depression and dry mouth.

Adrenergic receptor blockers PH1.13

Adrenergic receptor antagonists block the effects of sympathetic stimulation and adrenergic agonists mediated through α- and β-receptors.

α-adrenergic blockers

Pharmacological effects of α-blockers ( fig. 2.24 )

They block α-receptors, thus inhibiting the α-receptor–mediated responses of sympathetic stimulation and adrenergic agonists.

Classification

Irreversible nonselective α-blocker

Phenoxybenzamine.

Phenoxybenzamine is a nonselective α-adrenergic blocker that blocks both α ₁ - and α ₂ -receptors. It binds covalently to α-receptors and causes irreversible blockade. It also inhibits the reuptake of NA into the adrenergic nerve endings. It also blocks histamine (H ₁ ), cholinergic and serotonin receptors at higher doses.

Pharmacological effects

1.
PVR is reduced due to blockade of vascular α ₁ -receptors; has predominant venodilating effect.
2.
Increased release of NA from the adrenergic nerve endings due to blockade of presynaptic α ₂ -receptors. This may cause cardiac stimulation and produce tachycardia, palpitation, cardiac arrhythmias, etc. Other effects shown in Fig. 2.24 .

Phenoxybenzamine is given orally or through slow i.v. infusion. It has a slow onset but long duration of action because of irreversible blockade of α-receptors. Its main use is in the treatment of pheochromocytoma. The side effects are postural hypotension (mainly due to venodilatation), tachycardia, palpitation, diarrhoea, nasal stuffiness, giddiness and impotence.

Reversible nonselective α-blockers

Phentolamine.

Phentolamine is an imidazoline derivative. It competitively blocks the effects of NA at both α ₁ - and α ₂ -adrenergic receptors (competitive antagonism). Venodilatation is more than arteriolar dilation. It can also block 5-hydroxytryptamine (5-HT) receptors, K ⁺ channels; causes histamine release from mast cells.

Phentolamine is given intravenously and has a rapid onset but short duration of action.

Adverse effects.

They include tachycardia, palpitation, arrhythmias; angina and MI may be precipitated.

Tolazoline.

Tolazoline is similar to phentolamine and is rarely used.

Other competitive, nonselective α-blockers are ergot alkaloids (ergotamine, ergotoxine) and hydrogenated ergot alkaloids (dihydroergotamine).

Selective α ₁ -blockers

Prazosin is a potent and selective α ₁ -adrenergic receptor blocker. It is given orally. It is well absorbed from GI tract but undergoes extensive first-pass metabolism. The effects of α-blockade are depicted in Fig. 2.24 . Unlike nonselective α-blockers, selective α ₁ -blockers produce minimal or no tachycardia (as presynaptic α ₂ -receptors are not blocked). It causes both arteriolar and venodilatation; arteriolar dilatation is more prominent.

Adverse effects.

First-dose phenomenon (mechanism): Within 30–90 minutes of oral administration of first dose of prazosin, postural hypotension and syncopal attacks may be seen. Therefore, the initial dose should be small (1 mg). It is usually given at bed time so that the patient remains in bed for several hours and the risk of syncopal attack is reduced.

It may cause nasal stuffiness, tachycardia, impaired ejaculation and impotence.

Other selective α ₁ -blockers

■
Terazosin is similar to prazosin, but less potent than prazosin. It is almost completely absorbed after oral administration and has a longer duration of action.
■
Doxazosin is the longest acting selective α ₁ -blocker. The haemodynamic effects, bioavailability and extent of metabolism are similar to prazosin.
■
Alfuzosin blocks all subtypes of α ₁ -receptors (α _1A , α _1B and α _1D ). It is orally effective and used in benign prostatic hyperplasia (BPH).
■
Tamsulosin is an uroselective α ₁ -blocker (α _1A ). At low doses, it reduces the resistance to flow of urine with little effect on BP. It is administered orally and is the preferred α ₁ -blocker for treatment of BPH in normotensive patients. It may cause retrograde ejaculation.
■
Silodosin is a selective α _1A -blocker; useful orally in BPH. The adverse effects are postural hypotension and retrograde ejaculation.

Therapeutic uses of α-blockers

1.
Pheochromocytoma: It is a tumour of adrenal medulla, which releases large amounts of adrenaline and NA. The signs and symptoms include a sudden and paroxysmal rise in BP with headache, palpitation and excessive sweating. The diagnosis of pheochromocytoma is usually made by estimating catecholamines, VMA and other metabolites in blood and urine (normal VMA: 4–8 mg per 24 hours urine sample), CT and MRI scan.
- The definitive treatment for pheochromocytoma is surgery. In the preoperative period, phenoxybenzamine is used to control hypertension and restore blood volume. It is a nonselective and irreversible α-blocker. Blockade of vascular α ₁ -receptors causes vasodilatation and fall in BP. It can also be used in inoperable cases of pheochromocytoma.
- β-Blockers (propranolol) are used to control the cardiac manifestations – tachycardia and arrhythmias due to excess catecholamines. β-Blockers should not be given alone in pheochromocytoma because the blockade of vascular β ₂ -receptors causes unopposed α ₁ -action which leads to severe rise in BP due to vasoconstriction. This may be fatal. Therefore, prior administration of α-receptor blocker is a must before giving β-blockers.
- Metyrosine is used as an adjuvant in pheochromocytoma. It inhibits tyrosine hydroxylase enzyme and reduces the synthesis of catecholamines.
- During surgery, handling of the tumour results in sudden release of large quantity of catecholamines, which may cause marked rise in BP that can be controlled by i.v. phentolamine. It is a nonselective α-blocker with rapid onset of action.
2.
Hypertensive emergencies: Intravenous phentolamine can be used in the following conditions, because of its rapid onset of action:
- ■
  To control hypertensive episodes intraoperatively during surgery of pheochromocytoma.
- ■
  To control hypertensive crisis due to clonidine withdrawal.
- ■
  To control hypertensive crisis due to ‘cheese reaction’.
3.
Essential hypertension: Among α-blockers, selective α ₁ -antagonists are preferred to nonselective α-blockers in the treatment of mild-to-moderate hypertension. Selective α ₁ -antagonists cause less tachycardia and have favourable effects on lipid profile.
4.
Benign prostatic hyperplasia: Selective α ₁ -blockers are used in BPH; they decrease tone of smooth muscle in the neck of bladder and prostate resulting in reduction in resistance to urinary flow. Prazosin, doxazosin, terazosin and alfuzosin are particularly useful in patients who also have hypertension. Tamsulosin is preferred for BPH in normotensive patients.
5.
Tissue necrosis: Phentolamine is infiltrated locally to prevent tissue necrosis due to extravasation of α-agonists.
6.
Male sexual dysfunction: Local injection of phentolamine with papaverine may be used in the treatment of male sexual dysfunction. PH1.40
7.
Other uses include congestive cardiac failure and peripheral vascular diseases.

Selective α ₂ -adrenergic blocker

Yohimbine.

Yohimbine is an alkaloid. It competitively blocks α ₂ -receptors. It also has 5-HT receptor blocking effect. It is an aphrodisiac, but is rarely used therapeutically.

β-adrenergic blockers

β-adrenergic antagonists block the β-receptor–mediated effects of sympathetic stimulation and adrenergic drugs.

Classification

Pindolol, acebutolol and labetalol have partial agonistic activity (intrinsic sympathomimetic activity [ISA]). They stimulate β-receptors partially in the absence of catecholamines.

Propranolol, pindolol, acebutolol, metoprolol and labetalol have membrane-stabilizing activity (local anaesthetic activity).

Mechanism of action.

Propranolol is the prototype drug. β-Blockers competitively block the β-receptor–mediated actions of catecholamines and other adrenergic agonists.

Pharmacological properties of β-blockers

1.
Cardiovascular system:
- (a)
  Heart: β-Blockers depress all cardiac properties.
  - (i)
    Decrease heart rate (negative chronotropic effect).
  - (ii)
    Decrease force of myocardial contractility (negative inotropic effect).
  - (iii)
    Decrease cardiac output.
  - (iv)
    Depress SA node and AV nodal activity.
  - (v)
    Increase refractory period of AV node.
  - (vi)
    Decrease conduction in atria and AV node (negative dromotropic effect).
  - (vii)
    Decrease automaticity of ectopic foci.
  - (viii)
    Decrease cardiac work, thus reduce O ₂ requirement of the myocardium. Only in high doses, some of them have membrane-stabilizing effect.
- (b)
  Blood vessels: Blockade of β ₂ -receptors of blood vessels initially may cause rise in PVR due to unopposed α ₁ -action. However, continued administration of these drugs leads to a fall in PVR in patients with hypertension due to chronic reduction in cardiac output. Both systolic and diastolic BP is reduced.
- (c)
  They also reduce the release of renin from juxtaglomerular apparatus due to blockade of β ₁ -receptors and decrease central sympathetic outflow.
2.
Respiratory system: Blockade of β ₂ -receptors in bronchial smooth muscle can produce severe bronchospasm in patients with COPD and asthma. Therefore, β-blockers should be avoided in patients with asthma and COPD. Selective β ₁ -blockers such as atenolol and metoprolol are less likely to cause bronchospasm.
3.
Skeletal muscle: On chronic use, β-blockers may cause skeletal muscle weakness and tiredness due to blockade of β ₂ -receptors of the skeletal muscle and blood vessels supplying it. They also reduce stress-induced tremors.
4.
Metabolic effects: β-Blockers inhibit glycogenolysis and delay recovery from hypoglycaemia. They also mask the warning signs and symptoms of hypoglycaemia. Therefore, β-blockers should be used cautiously in diabetes patients on hypoglycaemic agents. Chronic use of nonselective β-blockers decreases high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol ratio which may increase the risk of coronary artery disease.
5.
Eye: β-Blockers on topical administration decrease IOP by reducing the secretion of aqueous humour (see p. 58).

Pharmacokinetics.

Propranolol is highly lipid soluble and is well absorbed from GI tract. However, the bioavailability of propranolol is low because of its extensive first-pass metabolism. It is highly bound to plasma proteins; has large volume of distribution; freely crosses BBB, and metabolites are excreted in urine.

Adverse effects of β-blockers.

They are mainly an extension of pharmacological actions.

1.
CVS:
- ■
  Bradycardia, heart block and may precipitate congestive heart failure in patients with low-cardiac reserve.
- ■
  Blockade of vascular β ₂ -receptors causes unopposed α ₁ -action, reduces further blood supply and may worsen peripheral vascular disease.
- ■
  β-Blockers can exacerbate Prinzmetal angina (variant angina) due to unopposed α ₁ -action, hence are contraindicated (see p. 117) in this condition.
2.
Respiratory system: Blockade of β ₂ -receptors in the bronchial smooth muscle can cause severe bronchospasm in patients with asthma and COPD. Hence, β-blockers are contraindicated in the above conditions.
3.
CNS: Sleep disturbances, hallucinations, fatigue and mental depression.
4.
Metabolic: Recovery from hypoglycaemia (induced by antidiabetic drugs) is delayed by β-blockers. β-Blockers may mask the warning signs and symptoms of hypoglycaemia.
5.
Muscular weakness and tiredness: These are due to reduced blood flow to skeletal muscle.
6.
Withdrawal symptoms: Abrupt withdrawal of β-blockers after chronic use is dangerous because angina or frank myocardial infarction (MI) and even sudden death can occur. This is due to upregulation (supersensitivity) of β-receptors in response to prolonged blockade (see p. 27).

Drug interactions

1.
Propranolol × verapamil: They produce additive cardiac depressant effects and may cause CCF, bradyarrhythmias, heart block or even cardiac arrest.
2.
Insulin/sulphonylureas × β -blockers: Nonselective β-blockers inhibit glycogenolysis and delay recovery from hypoglycaemia ( Fig. 2.25 ). They mask warning signs and symptoms of hypoglycaemia.
Fig. 2.25
Interaction between insulin/sulphonylureas and β-blockers.
3.
Cholestyramine and colestipol × β -blockers: Cholestyramine and colestipol are bile acid–binding resins. They bind to β-blockers in the gut and interfere with the absorption of β-blockers.
4.
Propranolol × lignocaine: Propranolol reduces the clearance of lignocaine by decreasing hepatic blood flow.
5.
Propranolol × NSAIDs: NSAIDs by inhibiting PG synthesis promote Na ⁺ and water retention on chronic use. Thus, they decrease antihypertensive effect of β-blockers.
6.
Propranolol × chlorpromazine: Propranolol interferes with the first-pass metabolism of chlorpromazine and increases its bioavailability.

Therapeutic uses of β-blockers

1.
Hypertension: β-Blockers are useful for all grades of hypertension. These drugs are preferred especially in patients with angina, MI or cardiac arrhythmias (see p. 105).
- The advantages of β-blockers are as follows:
  - ■
    Sodium and water retention is rare.
  - ■
    Cheaper.
  - ■
    Have a long duration of action.
  - ■
    Well tolerated.
2.
Angina prophylaxis and MI: β-Blockers reduce myocardial O ₂ demand by decreasing heart rate, myocardial contractility and arterial pressure. They improve exercise tolerance and reduce frequency of anginal episodes. Use of β-blockers early in acute phase of MI may limit infarct size. Long-term use of β-blockers may reduce mortality and reinfarction.
3.
Cardiac arrhythmias: β-Blockers are mainly used in atrial arrhythmias such as atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia (PSVT) but rarely for ventricular arrhythmias (see p. 135).
4.
Congestive cardiac failure (see p. 125): Chronic use of β-blockers such as carvedilol, metoprolol and bisoprolol has shown to reduce mortality rate in chronic heart failure.
5.
Pheochromocytoma: β-Blockers are used to control the cardiac manifestations of pheochromocytoma, but should not be given alone (see p. 90-91).
6.
Glaucoma (p. 58) : β-Blockers decrease the IOP by reducing the production of aqueous humour. Timolol, carteolol, levobunolol, betaxolol, etc. are used topically in glaucoma. Timolol is the most frequently used β-blocker in glaucoma. Betaxolol is a selective β ₁ -blocker; hence, systemic adverse effects (cardiovascular and pulmonary) are rare.
7.
Prophylaxis of migraine: Propranolol and metoprolol are effective in reducing the frequency of migraine headache. The mechanism is not known.
8.
Hyperthyroidism: The signs and symptoms of hyperthyroidism such as tachycardia, palpitation, tremor and anxiety are reduced due to blockade of β-receptors. Propranolol inhibits the peripheral conversion of T ₄ to T ₃ . It is also used in thyroid storm.
9.
Essential tremors: Oral propranolol may give some benefit in patients with essential tremors.
10.
Acute anxiety states: β-Blockers are useful in controlling the symptoms of acute anxiety such as palpitation, tachycardia, tremor and sweating.
11.
Alcohol withdrawal: Propranolol may produce some benefit in the treatment of alcohol withdrawal.
12.
Hypertrophic obstructive cardiomyopathy: Propranolol decreases outflow resistance.
13.
Dissecting aortic aneurysm: β-Blockers are useful in the management of dissecting aortic aneurysm – they decrease cardiac contractility and the rate of development of pressure during systole.

Important features of β-blockers are given in Table 2.12 .

Table 2.12 ■

β-Blockers with important features

β-Blocker	ISA	MSA	Lipid solubility	Route(s)	Daily dose (mg)
Propranolol	–	++	High	Oral, i.v.	20–400
Timolol	–	–	Moderate	Oral, topical (eye drops)	10–40
Nadolol	–	–	Low	Oral	20–160
Pindolol	++	+	Low	Oral	10–60
Atenolol	–	–	Low	Oral	25–200
Acebutolol	+	+	Low	Oral, i.v.	200–1000
Esmolol	–	–	Low	i.v.	0.5 mg/kg stat. 0.05–2 mg/kg/min infusion
Metoprolol	–	+	Moderate	Oral, i.v.	50–200
Bisoprolol	–	–	Low	Oral	2.5–10
Labetalol	+	+	Low	Oral, i.v.	200–1000
Carvedilol	–	++	Moderate	Oral	12.5–100
Celiprolol	+	–	Low	Oral	200–500
Betaxolol	–	+	Moderate	Oral	10–40
Nebivolol	–	–	Low	Oral	2.5–5

Note: Both atenolol and metoprolol have preparation of active enantiomer S (−); require half the dose of their racemate.

ISA, intrinsic sympathomimetic activity; MSA, membrane-stabilizing activity; –, no activity; +, some activity; ++, moderate activity.

Selective β ₁ -adrenergic blockers

Selective β ₁ -blockers have a lower risk of bronchoconstriction, less effect on carbohydrate metabolism, lipid profile and exercise capacity.

Esmolol

■
It is administered intravenously.
■
It is rapidly metabolized by esterases in RBCs; t _1/2 is about 10 minutes.
■
It has no membrane-stabilizing effect; no intrinsic sympathomimetic activity.
■
It is a selective β ₁ -blocker and has short duration of action.

Esmolol is used for rapid control of ventricular rate in supraventricular arrhythmias. It is also useful in hypertensive emergencies.

Atenolol

See Table 2.13 .

Table 2.13 ■

Differences between propranolol and atenolol

Propranolol	Atenolol
It is a nonselective β-blocker	It is a selective β ₁ -blocker
In large doses, it has membrane-stabilizing effect (local anaesthetic)	It has no membrane-stabilizing effect
It is highly lipid soluble, freely crosses BBB and produces central side effects (sleep disturbances, depression)	It is poorly lipid soluble, hence central side effects are rare
It has shorter duration of action, but propranolol SR formulation has a duration of 24 hours	It has longer duration of action, given once daily
It is less potent	It is more potent
Effective in suppressing essential tremors	Ineffective in essential tremors

β-Blockers with additional vasodilatory action

Labetalol

It is a competitive blocker at β ₁ -, β ₂ - and α ₁ -adrenergic receptors. In addition, it has partial agonistic activity (ISA) at β ₂ -receptors. It is administered orally or intravenously. It undergoes extensive first-pass metabolism after oral administration; hence, its bioavailability is poor. Oral labetalol is useful in the treatment of essential hypertension and i.v. labetalol for hypertensive emergencies. It is safe for use during pregnancy. The important side effects are postural hypotension and hepatotoxicity.

Carvedilol

Like labetalol, it also blocks β ₁ -, β ₂ - and α ₁ -adrenergic receptors. In addition, carvedilol has antioxidant, antiproliferative, membrane-stabilizing and vasodilatory properties; has no intrinsic sympathomimetic activity. It has cardioprotective effect; hence, long-term use reduces mortality in patients with CHF.

Celiprolol

It is a third-generation selective β ₁ -blocker and has weak vasodilating (due to nitric oxide release) and bronchodilating effects (β ₂ -agonism); has no membrane-stabilizing effect. It is effective in the treatment of hypertension and angina.

Nebivolol

■
Third-generation selective β ₁ -blocker.
■
Has (NO-mediated) vasodilating activity.
■
No membrane-stabilizing effect.
■
No intrinsic sympathomimetic activity.
■
No unfavourable effect on lipid profile.
■
It is used for control of hypertension and congestive cardiac failure.

Beta-blockers with intrinsic sympathomimetic activity (e.g. pindolol, acebutolol)

They are less likely to cause withdrawal symptoms, bradycardia and alteration of lipid profile.

Pharmacology for Medical Graduates, 4th Updated Edition

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Autonomic pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

Introduction to autonomic nervous system

Cholinergic system PH1.14

Cholinergic transmission

Synthesis of acetylcholine ( fig. 2.3 )

Cholinesterases

Cholinergic receptors

Cholinergic agents (cholinomimetics, parasympathomimetics) PH1.14

Classification

Choline esters

Acetylcholine.

Muscarinic actions

Nicotinic actions.

Bethanechol (table 2.3).

Cholinomimetic alkaloids

Pilocarpine.

Uses

Adverse effects.

Muscarine.

Arecoline.

Anticholinesterases ( fig. 2.11 )

Reversible anticholinesterases

Physostigmine (eserine).

Uses

Neostigmine ( table 2.4 ; see fig. 2.13 ).

Indirect actions.

Direct actions.

Pyridostigmine.

Edrophonium.

Uses

Adverse effects of anticholinesterases.

Therapeutic uses of reversible anticholinesterases

1. Glaucoma.

2. Myasthenia gravis.

Treatment.

3. Postoperative urinary retention and paralytic ileus ( fig. 2.13 ).

4. Curare poisoning and reversal of nondepolarizing neuromuscular blockade (see p. 74).

5. Belladonna poisoning (see p. 67).

6. Alzheimer’s disease.

Irreversible anticholinesterases PH1.51, PH1.52

Organophosphorus insecticides.

Signs and symptoms

Diagnosis.

Treatment.

Specific measures

Anticholinergic agents PH1.14

Antimuscarinic agents (muscarinic receptor antagonists) PH1.14

Mechanism of action.

Classification of antimuscarinic agents

Atropine.

Pharmacological actions of atropine ( fig. 2.14 )

Pharmacokinetics.

Atropine substitutes: Atropine acts on all subtypes of muscarinic receptors.

Therapeutic uses of atropine and its substitutes

Adverse effects and contraindications.

Scopolamine.

Drug interactions of anticholinergics.

Ganglion blockers

Skeletal muscle relaxants PH1.15

Physiology of skeletal muscle contraction

Classification

Centrally acting skeletal muscle relaxants

Neuromuscular blockers

Depolarizing blockers: Succinylcholine (suxamethonium).

Adverse effects

Competitive blockers (nondepolarizing blockers; table 2.8 ).

Mechanism of action.

Actions.

Pharmacokinetics.

Adverse effects.

Drug interactions of skeletal muscle relaxants

Factors affecting action of neuromuscular blockers

Uses

Reversal of neuromuscular blockade.

Sugammadex.

Directly acting skeletal muscle relaxant: Dantrolene.

Adrenaline (epinephrine): α _1- , α _2- , β _1- , β _2- and β ₃ -agonist.

Noradrenaline: α ₁ -, α ₂ - and β ₁ -agonist.

Isoprenaline (isoproterenol): β ₁ -β ₂ and β ₃ -agonist.

Dobutamine: Relatively selective β ₁ -agonist.

Salbutamol, terbutaline, salmeterol, formoterol: Selective β ₂ -adrenergic agonists.

Ritodrine: Selective β ₂ -agonist with main action on uterus.

Adverse effects of selective β ₂ -agonists

Phenylephrine, methoxamine, mephentermine: Selective α ₁ -adrenergic agonists

Selective α ₂ -adrenergic agonists.

Dopamine: α ₁₋ , α ₂₋ , β ₁₋ , and D ₁ -agonist with na release.

Selective α ₁ -blockers

Other selective α ₁ -blockers

Selective α ₂ -adrenergic blocker

Selective β ₁ -adrenergic blockers